The acute and chronic molecular effects of mild TBI (mTBI) have not been well studied or characterized. Over the past several decades it has become increasingly clear that repetitive mTBI is capable of altering the biochemical activity of the brain in ways that cannot be detected by current methodologies. Highlighting this issue is the definitive link between repeated mTBI and the development of chronic traumatic encephalopathy (CTE) in athletes and soldiers. The immediate issue facing an individual that has suffered a mTBI is determining when it is safe to return to high risk activities after a concussive injury without risking permanent brain damage that occurs at a cellular level. Unfortunately, no non-invasive diagnostic methods or tools currently exist to evaluate TBI-caused neuronal damage or CTE progression.
MicroRNAs (“miRNAs”) are endogenous, non-coding small RNAs approximately 22 base pair in length. MiRNAs are highly conserved across species, accounting for 1-2% of the genes in eukaryotic genomes while potentially regulating 30% of all annotated human genes. Mature miRNAs bind sequence-specific sites in the 3′-untranslated region (3′-UTR) of their target mRNAs and inhibit protein synthesis by repressing translation or regulating mRNA degradation. Some single miRNA have been predicted to regulate several hundred-target mRNAs. MiRNAs are important epigenetic regulators of biological processes and many are expressed specifically in an organ, cell or cellular compartment. The discovery that circulating miRNAs are altered in pathological conditions has spawned the development of miRNAs as potential biomarkers of neurodegenerative diseases. The release of miRNAs whether passive, associated with Argonaut2 (ago2) or mediated by active secretion via exosomes or microvesicles is believed to dramatically effect protein expression throughout the central nervous system. In the case of CTE, the definitive diagnosis of the disease is made post-mortem by the identification of neuronal death in specific areas of the brain e.g., cerebral hemispheres, thalamus and medial temporal lobe. However profound loss of neurons and brain atrophy are late-occurring events in the pathogenesis of the disease and are preceded by metabolic changes such as hyperphosphorylation of tau and deposition of neurofibrillary tangles presumably leading to synaptic dysfunction and loss, neurite retraction and axonal degeneration. Such damage has been demonstrated to release stable miRNA into the systemic circulation.